rs140214637
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The ENST00000359321.2(XRCC2):āc.283A>Gā(p.Ile95Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I95L) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000359321.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
XRCC2 | NM_005431.2 | c.283A>G | p.Ile95Val | missense_variant | 3/3 | ENST00000359321.2 | NP_005422.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
XRCC2 | ENST00000359321.2 | c.283A>G | p.Ile95Val | missense_variant | 3/3 | 1 | NM_005431.2 | ENSP00000352271 | P1 | |
XRCC2 | ENST00000495707.1 | n.305A>G | non_coding_transcript_exon_variant | 3/3 | 1 | |||||
XRCC2 | ENST00000698506.1 | c.115A>G | p.Ile39Val | missense_variant | 2/2 | ENSP00000513758 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000243 AC: 61AN: 250976Hom.: 0 AF XY: 0.000251 AC XY: 34AN XY: 135674
GnomAD4 exome AF: 0.000422 AC: 617AN: 1461522Hom.: 0 Cov.: 32 AF XY: 0.000432 AC XY: 314AN XY: 727058
GnomAD4 genome AF: 0.000151 AC: 23AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74376
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | May 02, 2012 | Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 95 of the XRCC2 protein (p.Ile95Val). This variant is present in population databases (rs140214637, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and pancreatic cancer (PMID: 22464251, 23054243, 26689913, 28767289). ClinVar contains an entry for this variant (Variation ID: 127954). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt XRCC2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect XRCC2 function (PMID: 27233470). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 02, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 17, 2020 | - - |
Fanconi anemia complementation group U Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
XRCC2-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 08, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at